Recalcitrant Trichomonas vaginalis infection--a case series.

The objective of this study was (1) to estimate the prevalence of recalcitrant Trichomonas vaginalis (TV) infection in a UK genitourinary medicine clinic; (2) to use a case series and literature review to suggest an algorithm for management of recalcitrant TV (rTV). A retrospective review of laboratory records, case-notes and literature review was conducted. Fifteen patients were studied, representing 1.16% of the cases presenting during the study period. A wide variety of therapeutic agents was used, the treatment regimen differed for each patient. No treatment was universally effective in achieving cure, but the use of acetarsol pessaries vaginally appeared to be the most frequently successful strategy. Based on these results, an algorithm for treatment of rTV is presented, although clinical trials will be needed to elucidate the best clinical approaches to this problem.

Molecular correlates in AIDS patients following antiretroviral therapy: diversified T-cell receptor repertoires and in vivo control of cytomegalovirus replication.

OBJECTIVES: To evaluate whether successful, long-term immune reconstitution in vivo can be achieved in end-stage AIDS patients following antiretroviral therapy (ART). METHODS: A 1-year prospective study of changes of CD4+ and CD8+ T-cell surface phenotypes, T-cell receptor (TCR) repertoires and capacity to control in vivo replication of cytomegalovirus (CMV) was performed in five treatment-naive end-stage AIDS patients (median CD4+ T-cell counts of 19 cells/microL) following therapy. Proportions of CD45RA+, CD45RO+ and CD28+ cells within the CD4+ and CD8+ subsets, were determined by flow cytometry. Changes in TCR Vbeta repertoires within the CD4+ and CD8+ T-cell compartments were evaluated using CDR3 spectratyping. CMV replication was determined by a sensitive polymerase chain reaction (PCR) assay using whole blood. RESULTS: Following ART, proportionate increases in 'naive' (CD45RA+) and 'memory' (CD45RO+) T cells were observed within both CD4+ and CD8+ T-cell subsets, while increased numbers of CD28+ T cells were mainly observed within the CD4+ subset. Diversification of CD4+ and CD8+ TCR repertoires was established concomitantly with renewed in vivo control of CMV replication. CONCLUSIONS: An important degree of molecular and functional immune recovery is possible in end-stage AIDS patients introduced to therapy. Diversification of TCR repertoires and the in vivo restoration of immunocompetence to control opportunistic infections clearly show that an important degree of molecular immune reconstitution is established following the initiation of ART even in late-stage AIDS.

Changing trends in cytomegalovirus disease in HIV-infected patients.

Treatment with combination antiretroviral therapy has transformed the natural history of human immunodeficiency virus (HIV) infection. Effective antiretroviral therapy results in both reduced risk of cytomegalovirus (CMV) disease and prolonged survival following CMV disease. These effects seem to be mediated by the reconstitution of immune responses against CMV, which results in re-established host control of CMV replication. As a result, some individuals have been able to discontinue maintenance therapy for CMV with a low risk of disease recurrence to date. The risk of development or progression reappears in the context of antiretroviral failure--a problem increasingly recognized in clinical practice. However, improved immune function is not always beneficial. Indeed, previously uncommon inflammatory complications have been associated with immune reconstitution following highly active antiretroviral therapy. The natural history of CMV disease at a time of rapid changes in treatment strategies remains uncertain and, therefore, individuals at risk continue to require careful management.

Changes in the natural history of cytomegalovirus retinitis following the introduction of highly active antiretroviral therapy.

OBJECTIVE: To determine the effect of highly active antiretroviral therapy (HAART) on the natural history of cytomegalovirus (CMV) retinitis. DESIGN AND PARTICIPANTS: Retrospective analysis of 103 consecutive patients diagnosed with CMV retinitis between 1990 and 1998. SETTING: Specialist HIV medicine department of a London hospital. MAIN OUTCOME MEASURES: Incidence of CMV retinitis, time to death following diagnosis, episodes of progression, incidence of inflammatory complications. The date of first use of HAART was January 1995. Data were censored on 30 June 1998. RESULTS: The incidence of CMV retinitis has declined dramatically following the introduction of HAART. Survival following CMV retinitis increased from a median of 0.65 years prior to 1995 to a median of 1.07 years after this date (P = 0.004). In multivariate analyses HAART was independently associated with improved survival (P = 0.02) and the association with year of diagnosis was no longer significant, suggesting that this effect is predominantly due to HAART. None of the patients receiving HAART experienced progression after 6 months of treatment. Complications of retinitis such as retinal detachment, uveitis and optic atrophy occurred in 39% of patients. The rare inflammatory complications of vitritis and cystoid macular oedema occurred only in recipients of HAART. CONCLUSIONS: The introduction of HAART has had a major impact on the natural history of CMV retinitis with improved survival time and decreased risk of progression following diagnosis. However, immune reconstitution may be associated with inflammatory complications which can result in significant visual loss in the absence of active CMV disease.

Response of asymptomatic cytomegalovirus viraemia to oral ganciclovir 3 g/day or 6 g/day in HIV-infected patients.

Reactivation of cytomegalovirus (CMV) following immunosuppression may result in the development of CMV disease and is associated with an increased risk of death. CMV viraemia detected by the polymerase chain reaction (PCR) precedes CMV disease in HIV-infected patients and identifies individuals at high risk of disease. Pre-emptive ganciclovir (GCV) therapy in patients who have evidence of CMV viraemia is effective in preventing disease. An open study was conducted to assess the response of CMV viraemia to oral GCV at a dose of 3 or 6 g/day for 28 days. HIV RNA was measured to determine if CMV inhibition affected HIV viral load. Fourteen patients were studied, three of whom entered both phases of the study. None of the patients had evidence of CMV disease at the time of entry into the trial; two patients developed CMV retinitis after completion of the trial. Oral GCV at both 3 and 6 g/day caused a decrease in CMV viral load in individual patients. However, a rebound in CMV viral load occurred in patients receiving the 3-g/day dose. None of the patients receiving oral GCV 3 g/day became PCR negative after 21 days compared with six of eight patients receiving 6 g/day. Five of eight patients (63%) receiving GCV 6 g/day were concurrently taking protease inhibitors compared with two of nine (22%) receiving 3 g/day. Ten patients remained PCR negative throughout follow up. No change was found in HIV viral load during receipt of GCV at either dose. Thus, oral GCV is effective in reducing CMV viral load, but a dose of 3 g/day is insufficiently potent for pre-emptive therapy.

Changes in AIDS-defining illnesses in a London Clinic, 1987-1998.

OBJECTIVES: To describe the incidence of AIDS-defining illnesses within a single large clinic setting, to describe temporal changes over a 10-year period in the overall incidence and of individual AIDS-defining illnesses and to investigate the impact of HIV treatment regimen on the incidence of AIDS-defining illnesses. SUBJECTS AND METHODS: A person-years analysis was used to determine the incidence of AIDS-defining illnesses according to calendar year and stratification by CD4 lymphocyte count and treatment regimen in 1806 patients from the Royal Free Centre for HIV Medicine with at least one CD4 lymphocyte count and follow-up visit. RESULTS: Prior to 1992, the incidence of all AIDS-defining illnesses was 27.4/100 person-years of follow-up (PYFU; 95% confidence interval [CI], 22.8-32.0) and during 1997 this incidence had dropped to 6.9/100 PYFU (95% CI, 4.7-9.1; p < .0001, test for trend). The decline in incidence over time occurred in esophageal candidiasis, cytomegalovirus disease (including retinitis), Kaposi's sarcoma, lymphoma, wasting syndrome, and Pneumocystis carinii pneumonia (p < .05, test for trend), but there was no evidence of a decline in AIDS dementia or in Mycobacterium avium complex. In 1997, among patients with CD4 lymphocyte counts of < or =200 cells/mm3, the incidence rates for any AIDS-defining illness was 51.1/100 PYFU for patients taking no therapy (95% CI, 27.9-85.7), 34.5 among patients on monotherapy (95% CI, 4.2-124.6), 13.2 among patients taking dual combination therapy (95% CI, 3.6-33.8) and 6.1 among patients taking triple therapy or more complex regimens (95% CI, 0.7-22.0; p < .0001, test for trend). CONCLUSIONS: There was a considerable decline in AIDS-defining illnesses during 1996 and 1997, coinciding with the rapid development of new antiretroviral treatments and combinations of treatment. Further follow-up of large observational cohorts is essential to monitor the incidence of diagnoses less common than we were able to consider, such as tuberculosis, cryptosporidiosis, and cryptococcosis, and also to investigate whether the incidence of disease continues to fall, or whether it starts to rise again, as toxicities, compliance, drug resistance, and long-term side effects begin to appear.

Shorter survival in HIV-positive patients with diarrhoea who excrete adenovirus from the GI tract.

Adenoviruses have been described as a cause of diarrhoea in patients infected with the human immunodeficiency virus (HIV). The prevalence of adenoviruses was studied in all HIV-positive patients presenting with diarrhoea at the Royal Free Hospital in London between 1991 and 1995. In addition, all postmortems carried out in HIV-positive individuals registered at the same centre between 1990 and 1997 were reviewed for evidence of adenovirus infection. Adenovirus was detected in 16.1% of patients presenting with diarrhoea. These individuals had a significantly lower CD4 count and were more likely to have had a diagnosis of acquired immunodeficiency syndrome (AIDS) than patients with diarrhoea in whom adenovirus was not detected. The median survival was 1 year compared with 2.4 years for those without adenoviruses; this difference remained significant (P = .008) after controlling for differences in CD4 counts between the groups. Gastrointestinal adenovirus excretion occurs at an advanced stage of HIV disease, and is associated with a poor prognosis. We suggest that adenoviruses may contribute to mortality in this population.

Loss of cytomegalovirus (CMV) viraemia following highly active antiretroviral therapy in the absence of specific anti-CMV therapy.

OBJECTIVE: To determine the effect of highly active antiretroviral therapy (HAART) on cytomegalovirus (CMV) viraemia and retinitis in patients at high risk of disease. DESIGN: Sixteen patients with CMV viraemia, but no evidence of end organ disease at the time of first receipt of HAART including a protease inhibitor, were studied. No patient had ever received specific anti-CMV therapy. METHODS: CMV load in blood was measured using quantitative competitive PCR at baseline and for a median follow-up of 21 months. Regular ophthalmological screening for retinitis was conducted throughout the study period. RESULTS: All 16 patients became CMV negative by PCR following the commencement of HAART. CMV loads prior to treatment ranged from 2.0 x 10(3) to 4.1 x 10(6) copies/ml (median, 7.6 x 10(4) copies/ml). The median time to becoming PCR negative was 13.5 weeks (range, 5-40 weeks). Fourteen patients remained CMV negative throughout follow-up. CMV viraemia recurred in two patients; these individuals were indistinguishable with respect to either baseline parameters or response to antiretroviral therapy. None of the 16 patients developed CMV retinitis. CONCLUSIONS: HAART including a protease inhibitor can result in the complete suppression of CMV viraemia, an effect not previously observed in HIV-infected patients in the absence of specific anti-CMV therapy. This response correlated with protection against CMV retinitis in a group of patients at high risk of development of disease. These results help to explain why the natural history of CMV disease has altered since the introduction of such therapeutic regimens.

Continuous intrafetal infusion of prostaglandin E2 prematurely activates the hypothalamo-pituitary-adrenal axis and induces parturition in sheep.

This study has investigated the effect of continuous intrafetal infusion of PGE2 or saline on hormone concentrations and the length of gestation in sheep. Fetal and maternal vascular catheters were surgically implanted at 112.3 +/- 1.3 days (n = 10), and the infusions were started at 121 +/- 1.2 days of gestation (term = 147). Fetuses were infused with either PGE2 (n = 5; 2 micrograms/min for 48 h and then increased to 4 micrograms/min for the remainder of the experiment) or the vehicle solution (n = 5; sterile isotonic saline) via the fetal carotid artery. In the PGE2-infused group, fetal and maternal plasma PGE2 concentrations increased (P < 0.001) after the change to the higher dose rate (4 micrograms/min) and remained elevated, fetal plasma immunoreactive ACTH (ir-ACTH) concentrations dramatically increased after the start of the infusion being maximal at 11 h before decreasing to match concentrations exhibited by the saline-infused group. Fetal plasma cortisol concentrations increased after the start of the PGE2 infusion (P = 0.05) and increased further after the change to the higher dose rate of 4 micrograms/min (P < 0.001). Concentrations of PGE2, ir-ACTH, and cortisol in the saline-infused group did not change until labor. Plasma concentrations of PGE2 (P < 0.001) and ir-ACTH (P < 0.005) increased on the day of labor in both treatment groups, and fetal cortisol concentrations increased (P < 0.001) in both groups in the last few days before labor. The proportion of low molecular weight ir-ACTH in the plasma of PGE2-infused fetuses was significantly higher than that of saline-infused fetuses (P < 0.001) during the first 15 days of infusion. In the saline-infused group, the proportion of low molecular weight ir-ACTH increased in the last few days before labour (P = 0.001), whereas no change was seen in PGE2-infused fetuses at this time. Maternal plasma progesterone concentrations decreased in both groups in the last few days before labor (P < 0.001). Fetuses infused with PGE2 delivered at 138.4 +/- 2.1 days, whereas control fetuses infused with saline delivered at 148.2 +/- 0.5 days (P < 0.001). The spontaneous increase in PGE2 preceding normal labor may thus play an important role in activation and maturation of the hypothalamic-pituitary-adrenal axis in fetal sheep.

Prostaglandin E2 administered to fetal sheep increases the plasma concentration of adrenocorticotropin (ACTH) and the proportion of ACTH in low molecular weight forms.

This study investigated the effects of repeated short term (2-h) intrafetal infusions of prostaglandin E2 (PGE2) on ACTH and cortisol release in fetal sheep during late gestation (119-144 days). We compared the effects of administration of PGE2 (2 micrograms/min) into the fetal carotid artery or jugular vein. PGE2 infusion significantly (P < 0.001) increased fetal plasma immunoreactive (ir-) ACTH and cortisol concentrations regardless of the vessel used for administration. Saline infusion did not alter the concentrations of ir-ACTH or cortisol for the duration of the experiment. To compare the responses of fetal ir-ACTH and cortisol to repeated intracarotid infusions of PGE2, the hormone data were grouped into five gestational age ranges (119-125, 126-130, 131-135, 136-140, and 141-145 days). Fetal ir-ACTH was stimulated by PGE2 infusion at all gestational ages studied; the greatest response was achieved at the earliest gestational age range, 119-125 days. PGE2 infusion preferentially stimulated the release of low mol wt ACTH [ACTH-(1-39); 60 min from the start of infusion] at all gestational ages (P < 0.01), but basal low mol wt ACTH did not increase with gestational age until after 140 days. Cortisol concentrations were increased within 30 min of infusion at all gestational ages studied. These results suggest that PGE2 may play a role in maintaining elevated ir-ACTH concentrations in the face of high levels of cortisol in fetal sheep before parturition.

Effect of late hypothalamo-pituitary disconnection on the development of the HPA axis in the ovine fetus and the initiation of parturition.

The studies of Liggins et al. (1) in which fetuses stalk-sectioned from day 116 onwards delivered at or near term, suggested that a connection between the fetal hypothalamus and pituitary is not essential for parturition to occur. The objective of this study was to repeat these experiments on the effects of pituitary stalk sections at different gestational ages and include information on the plasma concentrations of key fetal hormones. We have used the more sophisticated technique of hypothalamo-pituitary disconnection (HPD) at either of two gestational age ranges (123-127 days or 133-135 days). Completeness of the procedure was assessed by demonstrating an attenuated prolactin response to chlorpromazine challenge. Following HPD, gestation was prolonged for at least eight days beyond term (146.2 +/- 1.5 days) in 9 of the 10 fetuses operated. Fetal plasma ACTH1-39 concentrations were not different between the HPD and control fetuses, increasing in all groups with increasing gestation. Fetal plasma cortisol concentrations increased (P < 0.01) in control fetuses over gestation. Cortisol concentrations did not change significantly in the day 125 HPD group following HPD but increased in the day 135 HPD group (P < 0.05) with advancing gestation. These latter concentrations, however were markedly less (P < 0.001) than those for control fetuses prior to parturition. Fetal and maternal plasma PGE2 concentrations increased (P < 0.01) in the control group over gestation but did not change following HPD. Maternal plasma progesterone concentrations decreased (P < 0.05) after day 143 in the control group but did not change in the HPD group.(ABSTRACT TRUNCATED AT 250 WORDS)

Circadian rhythms in sleep and wakefulness and in salivary melatonin and cortisol concentrations in mothers of term and preterm infants.

We compared the effects of the demands of term and preterm infants on the daily rhythms of sleep and wakefulness and salivary melatonin and cortisol concentrations in mothers for up to 5 months after either birth (term group) or arrival of the infant home (preterm group). Although there were relatively small differences between the term and preterm groups in the daily patterns of infant sleep-wake behavior, there were more marked differences in the maternal sleep-wake parameters. During the first 8 weeks after the arrival of the infant home, the mothers of preterm infants had significantly less time asleep and fewer sleep bouts per 24 hours than did the mothers of term infants. The mothers of preterm infants spent a significantly longer proportion of each night awake (30-40%) for the first 8 weeks than did the mothers of the term infants (20-30%). There was also a significant difference between the term and preterm groups in the effect of time of day on maternal salivary melatonin concentrations. In the term group, maternal melatonin concentrations were higher at night (10 p.m.-6 a.m.) than at any other time of day. In contrast, in the preterm group maternal melatonin concentrations between 10 p.m. and 6 a.m. were only higher than those measured between 6 a.m. and 2 p.m. Salivary cortisol concentrations were significantly higher in the mothers of preterm infants than in the mothers of term infants throughout the 10-week study period, but the peak in salivary cortisol concentrations occurred between 2 a.m. and 10 a.m. in both the term and preterm groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Early hypophysectomy of sheep fetuses: effects on growth, placental steroidogenesis and prostaglandin production.

The factors involved in the control of steroid secretion from the ovine placenta and in fetal growth are as yet unclear. We hypothesized that factors derived from the fetal pituitary may play a role in the production and release of placental steroids and in growth of the fetus, and have investigated the effects of fetal hypophysectomy performed between day 70 and day 79 of gestation (term = 147 days) on systemic concentrations of hormones derived from the placenta, and on fetal growth. Maternal peripheral progesterone, placental lactogen and uterine vein progesterone increased significantly from day 90 in all ewes. Peripheral concentrations of prostaglandin E2 and peripheral and uterine vein oestrone sulfate increased significantly in the control group but not in the fetal hypophysectomy group. Uterine vein prostaglandin E2 increased significantly after day 95 in the control group and after day 105 in the fetal hypophysectomy group. Early fetal hypophysectomy caused marked growth retardation. The weights of the brain, kidneys and liver of hypophysectomized fetuses were the same as those of controls suggesting that their growth is not under pituitary control. In contrast, the weights of heart and lungs were reduced in proportion to body weight, suggesting that heart, lung and carcass growth were under pituitary control. Our data indicate that the fetal pituitary influences the control of placental steroid and prostaglandin E2 biosynthesis after day 90 of gestation in sheep, but that output of other hormones such as placental lactogen is independent of pituitary control, and may determine organ-specific growth parameters that are unaffected by removal of the fetal pituitary.

Role of prostaglandins in the metabolic responses of the fetus to hypoxia.

OBJECTIVE: The effect of inhibiting prostaglandin synthesis on the fetal metabolic response to hypoxemia was examined by infusing indomethacin during periods of reduced maternal uterine blood flow. STUDY DESIGN: In seven fetal sheep we administered a 6-hour infusion of either indomethacin (n = 5), indomethacin plus prostaglandin E2, or a vehicle solution (n = 5). The last 4 hours of each infusion period coincided with a period of fetal hypoxemia induced by reduced maternal uterine blood flow. RESULTS: During reduced maternal uterine blood flow indomethacin infusions caused a significantly greater reduction in pHA (reduced from 7.36 +/- 0.01 to 7.10 +/- 0.02) than both the vehicle (from 7.36 +/- 0.01 to 7.20 +/- 0.03) and indomethacin plus prostaglandin E2 infusions (from 7.36 +/- 0.01 to 7.18 +/- 0.02). Before reduced maternal uterine blood flow was induced, indomethacin significantly elevated fetal plasma glucose and lactate concentrations from 0.6 +/- 0.04 and 2.2 +/- 0.1 to 1.3 +/- 0.2 and 6.7 +/- 0.7 mmol/L, respectively. During reduced maternal uterine blood flow indomethacin caused a significantly greater increase in plasma glucose and lactate concentrations than the vehicle; plasma glucose and lactate concentrations increased to a maximum of 1.8 +/- 0.2 and 22.7 +/- 0.8 mmol/L, respectively, during indomethacin infusions compared with 1.1 +/- 0.1 and 15.7 +/- 1.7 mmol/L, respectively, during vehicle infusions. The addition of prostaglandin E2 to the indomethacin infusion prevented the enhanced increase in glucose and lactate concentrations during reduced maternal uterine blood flow and caused a significant increase in fetal plasma insulin concentrations from 12.6 +/- 0.7 to 60.9 +/- 28.1 microU/ml. CONCLUSION: The inhibition of prostaglandin synthesis during fetal hypoxemia alters the metabolic response of the fetus, leading to a severe metabolic acidosis.

Development of circadian sleep-wake rhythms in preterm and full-term infants.

We have compared the roles of neurologic maturity and environmental time cues in the development of the entrained circadian sleep-wake rhythm in the preterm and term human infant. The preterm infants (n = 19) spent some time after birth in a hospital nursery with no environmental time cues, whereas the term infants (n = 22) were exposed from birth to a cyclical light and dark environment with one major caregiver. The circadian sleep-wake rhythm in the preterm infants entrained after a similar time of exposure to an environment with daily time cues but at an earlier postconceptional age when compared with the term group. We conclude, therefore, that it is the length of exposure to environmental time cues, rather than neurologic maturity, that determines the entrainment of the circadian rhythm of sleep and wakefulness in the human infant.

Fetal endocrine responses to prolonged hypoxemia in sheep.

Our aim was to characterize the pattern of release of epinephrine, norepinephrine, arginine vasopressin (AVP), cortisol (hydrocortisone), and prostaglandin E2 (PGE2) into the fetal circulation during prolonged reductions in uterine blood flow (RUBF). In five sheep RUBF was induced for 24 h, whereas in another five sheep (controls) uterine blood flow was not reduced. Fetal arterial oxygen saturation was decreased from 60.5 +/- 3.6 to 20.3 +/- 1.6% after 2 h of RUBF and remained significantly reduced for the entire RUBF period. The incidence of fetal breathing movements (FBM) and fetal arterial pH were reduced from 36.7 +/- 4.5 min/h and 7.36 +/- 0.01 to 4.3 +/- 1.8 min/h and 7.13 +/- 0.02, respectively, after 2 h of RUBF, but both had returned to control levels after 14 h. Fetal plasma AVP and epinephrine concentrations were increased from 4.4 +/- 0.5 pg/ml and 0.19 +/- 0.05 ng/ml to 333.8 +/- 41.5 pg/ml and 1.5 +/- 0.6 ng/ml, respectively, after 2 h and then declined to near control levels after 12 h of RUBF. Fetal plasma norepinephrine and cortisol concentrations were increased from 1.3 +/- 0.4 and 4.0 +/- 2.2 ng/ml to 6.1 +/- 1.8 and 13.5 +/- 4.1 ng/ml, respectively, after 2 h of RUBF, and both remained significantly elevated throughout the remainder of the RUBF period. Fetal plasma PGE2 concentrations progressively increased (from 1.9 +/- 0.4 to 8.8 +/- 1.7 nmol/l at 12 h) as the duration of RUBF increased and were still significantly elevated after 24 h. The time course for the increase in PGE2 during RUBF was very similar to the increases in arterial pH and in the incidence of FBM.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of morphine and naloxone on plasma prolactin concentrations in the fetal sheep and pregnant ewe during late gestation.

This study investigated the effects of intrafetal morphine or naloxone administration on fetal and maternal plasma prolactin concentrations in the sheep during late pregnancy (117-143 days gestation). After intravenous morphine (3 mg/kg) there was a significant increase (p less than 0.05) in fetal plasma prolactin concentrations which was sustained for 180 min post-injection. There was no significant effect of either gestational age (125-133 days compared to 134-143 days gestation) or repeated administration (up to 3 treatments) of morphine on the fetal prolactin response to morphine. Intrafetal administration of naloxone (3.8 mg/kg bolus + 9.9 mg/kg/60 min), blocked the fetal prolactin response to morphine. Maternal plasma concentrations of prolactin were significantly increased (p less than 0.05) at 180 min after the intrafetal morphine bolus. When naloxone alone was infused, there was no change in fetal plasma prolactin concentrations, but there was a significant fall (p less than 0.05) in maternal plasma prolactin from 25 min after the start of the naloxone infusion. Thus, acute administration of morphine is associated with fetal and maternal hyperprolactinaemia. Although the endogenous opioids do not appear to mediate basal prolactin secretion in the fetus, they may have a role in the control of prolactin release in the pregnant ewe during late gestation.